Dietary fatty acids are known to modulate immunological defense systems. However, underlying mechanisms for such modulation are not well understood. Results from our previous studies demonstrated that saturated fatty acids activate Toll-like receptors (TLRs) leading to NFkappaB activation and the expression of mitogen inducible cyclooxygenase (COX-2) in macrophages. However, all unsaturated fatty acids tested inhibit TLR activation induced by saturated fatty acids or bacterial lipopolysaccharide (LPS). N-3 polyunsaturated fatty acids (PUFAs) as compared with n-6 PUFAs preferentially inhibit the activation of TLRmediated signaling pathways and target gene expression in macrophages. These results document novel mechanism by which fatty acids modulate receptor-mediated signaling pathways and target gene expression, and suggest that TLR-mediated target gene expression and immune responses can be modulated by types of dietary fatty acids. The next question is what the functional consequence of this modulation is. TLRs play a major role in recognition of invading microbial pathogens and induction of innate and adaptive immune responses for elimination of infecting microbes. As a logical extension of our previous studies, we propose here to determine whether changes in the dietary fatty acid composition can alter immune responses and subsequent host defense against infection, and to elucidate the mechanisms by which fatty acids modulate infection-induced innate and adaptive immune responses. The specific aims are: 1) To determine mechanisms by which saturated fatty acids activate TLR4 and TLR2 dimers, but polyunsaturated fatty acids inhibit the activation. 2) To identify target genes that are differentially regulated by saturated and polyunsaturated fatty acids;3) To determine whether saturated and unsaturated fatty acids alter immune responses as a result of modulation of TLR-signaling pathways and target gene expression using animal models;4) To determine whether types of dietary fatty acids alter susceptibility of the host to bacterial infection in animal models. Results from proposed studies will provide a comprehensive picture as to how the modulation of TLR-derived signaling pathways and target gene expression by different types of fatty acids leads to differential immune responses and host defense against the invading microbial pathogens. In addition, the mechanistic information gained from these studies will enhance our understanding as to how infections can increase risks of developing certain chronic diseases and how such risks can be reduced by dietary means.